1. Diabetes Mellitus 101 for Medical Professionals
An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes:
Part 8
Stan Schwartz MD,FACP
Clinical Associate Professor of Medicine, U of Pa.
Cardiometabolic Institute
Penn-Presbyterian Hospital,, UPHS 1

2. Ranolazine (15mg/kg) Plasma Insulin (% of baseline) Vehicle
EFFECT OF RANOLAZINE ON PLASMA INSULIN RESPONSE DURING AN IVGTT IN NORMAL RATS
Dhalla et al, unpubl data (on file, CVT Pharm)
1800
Ranolazine
(15mg/kg)
1200
Plasma Insulin
(% of baseline)
600
Vehicle 10 20 30
Time (min)

3. EFFECT OF RANOLAZINE AND GLYBURIDE ON PLASMA GLUCOSE AND INSULIN CONCENTRATIONS IN NORMAL RATS: eg: GLUCOSE DEPENDENT INSULIN RELEASE
Dhalla et al, unpubl data (on file, CVT Pharm)
GLYBURIDE
RANOLAZINE
GLYBURIDE
RANOLAZINE 30 60 90
120 1 2 3
Glucose (mg/dl)
Plasma Insulin (mg/dl) 30 30 30 30
TIME (min)
Normal glycemia- no insulin release-
eg: GLUCOSE DEPENDENT INSULIN RELEASE

4. Insulin Release (% of control)
GLUCOSE DEPENDENCE OF THE EFFECT OF RANOLAZINE ONINSULIN SECRETION FROM HUMAN PANCREATIC ISLETS
Dhalla et al, unpubl data (on file, CVT Pharm)
P<0.05
400
300
Insulin Release
(% of control)
200
100
RAN
CON
CON
RAN
Glucose-3mM
Glucose-20mM

5. Insulin Release (% of control)
CONCENTRATION DEPENDENT EFFECT OF RANOLAZINE ON INSULIN SECRETION FROM HUMAN PANCREATIC ISLETS
Dhalla et al, unpubl data (on file, CVT Pharm)
P<0.01
450
P<0.05
300
Insulin Release
(% of control)
150
RAN
0 M
RAN
100 M
RAN
5 M
RAN
0 M
Glucose-3mM
Glucose-25mM

6. MECHANISM OF ACTION OF RANOLAZINE TO STIMULATE INSULIN SECRETION
Ranolazine inhibits late sodium current, resulting in decreased calcium overload in myocytes
The effect of inhibition of the sodium current on insulin secretion in pancreatic beta cells is unknown

7. Ranolazine may be VERY Beneficial in Patients With Diabetes
1. avoid hypoglycemic agents- use Metformin/Incretin/tzd//bromocryptine/ ranolazine for CV/ glucose
2. In patients with TZD edema, diastolic dysfunction benefit obviates Edema
3. Ranolazine / Incretins peri-op / peri-cath for cardio-protection
4. incretin/ranolazine similarities- heart/beta cell-
no additional benefit, additive, supra-additive

8. Ranolazine may be a preferred Anti-anginal in Patients With Diabetes
Beta-blockers increase blood sugar, decrease recognition of hypoglycemia, and increase risk of claudication, increase risk overt DM in non-diabetics- only have secondary outcome studies- decreases pulse/ bp
Calcium channel blockers can increase edema in those patients- who may have obesity-related venous insufficiency and may be on other meds that have edema risk (eg: TZD)-
no outcome studies- decreases BP
Nitrates prevent use of ED agents (high risk of ED in this population) – no outcome studies- decreases BP
4. ? Additive reduction in ACS with tzd/ ranolazine

9. Use of Ranolazine in Patients With Diabetes- ‘Issue of Silent Ischemia’
1. Real ‘Silent Ischemia’ -- in sense of neuropathy-related absence of chest discomfort
2. But ‘false’ ‘Silent Ischemia’-- in sense of they are likely to have:
a. symptomatic anginal ‘equivalents’
b. progressive reduction in exercise capability, and patient then limits activity to avoid symptoms
3. BOTH

10. ULTIMATELY,WITH MORE DATA, could see Use of Ranolazine in a large number of Patients With Diabetes who have - (with better supporting data)
Symtomatic Ischemia
‘Silent Ischemia’
ECHOS with decreased EF, diastolic dysfunction- edema with pio-
Hx CHF
History or risk for a.fib
Cardio-protection peri-op

11. Practical problem in increasing Ranolazine’s use
Overcome prior QT / arrhythmia worry
Overcome their impression of ‘less effective’ given previous use as last line agent where it worked ~50% of time
How to get cardiologist to use as first line for ischemia, esp. in dm- teach its glycemic benefit
Get more data to use in other situations mentioned
How to get primary/ endo’s comfortable in prescribing cardiac med without ‘offending cardiologists’

12. RANOLAZINE CAN BE USED IN PATIENTS WITH CAD AND DIABETES.
Ranolazine affects Na+ channel function in cardiomyocytes,
and is likely to do the same in beta-cells
Ranolazine is approved for treatment of ischemic anginal-equivalents
Ranolazine significantly and dose- dependently reduces HbA1c.
The magnitude of HbA1c lowering by ranolazine is correlated with the levels of HbA1c and FPG at baseline.
Ranexa does not increase the incidence of hypoglycemia compared with placebo
Ranexa does not increase the incidence of:
Weight gain
Cardiovascular adverse events
Dyslipidemia (LDL, HDL, total cholesterol, and
triglycerides)
No Clinically relevant changes in blood pressure or heart rate
Timmis AD, et al. Eur Heart J 2006;27:42-48